Phenocopying ATM loss via modulation of cellular metabolism to overcome resistance to the ATR inhibitor

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Our objectives are (i) to characterise the role of ATM in generating resistance toATR inhibitors by investigating the effect of ATM deficiency on cellular metabolism; (ii) to investigatewhether we can recreate the metabolic profile of ATM-deficient cells via targeting cellular metabolism and ifthis would sensitize cancer cells to AZ6738, mimicking ATM loss. Understand how ATM contributes togenerate resistance to AZ6738, a drug currently in clinical trials, our proposal is of clear relevance for thepharmaceutical industry and thus in the remit of BBSRC.Aim1: Using tracer compounds and unpublished preliminary data form AZ, we will investigate themechanisms responsible for the metabolic profile of ATM deficient cells.Aim2: inhibitors are already available for the majority of metabolic pathways, thus we will take advantage ofthis underexploited toolbox to mirror the ATM-deficient metabolic phenotype identified in Aim1 and test ifthis will sensitise ATM proficient cells to AZ6738.Aim3: in the cerebellar cortex of Ataxia-telangiectasia patients (carrying mutations in the ATM gene) a set ofmitochondrial genes is deregulated5. In collaboration with GS (UCL - second supervisor) we will identifycells with a similar mitochondrial phenotype using publicly available dataset (i.e. CCLE) and will test thesensitivity to AZ6738 of cells with different mitochondria phenotypes.Expected outcome: understand how changes in cellular metabolism may lead to drug resistance